Removal of low density lipoprotein from blood plasma using cross-linked, sulfated polyvinylalcohol

The properties of a new synthetic LDL binding material, consisting of fragments of loosely crosslinked hydrogel, based on sulfated polyvinylalcohol are described. When incubated with 20 times its volume of plasma, this material binds up to 95% of the LDL, even from plasma with severely elevated LDL cholesterol levels (up to 20 mM). In addition a cholesterol-rich subfraction of VLDL is bound but HDL is not bound. After about 10 min binder/plasma contact the LDL removal is complete and no other additives are required. LDL binding capacity is dependent on the average binder particle size, indicating a restricted penetration of LDL particles into the binder matrix

Hydrogels by irradiation of a synthetic heparinoid polyelectrolyte

Gamma irradiation of aqueous solutions of a synthetic heparinoid polyelectrolyte results in the formation of hydrogels, varying in water content and mechanical strength. The equilibrium water content and the mechanical strength of the hydrogels are dependent on the initial polyelectrolyte concentration, the molecular weight of the polyelectrolyte, the percentage of double bonds in the polyelectrolyte and the radiation dose.\ud \ud The polyelectrolyte hydrogels do not deplete Antithrombin III from blood and there is no activation of factor XII according to an in vitro kallikrein generation test. However, in a very sensitive test for factor XII activation (contact promoted shortening of the thrombotest) a slight activation of this factor was observed

Genetic analysis of indicators of cholesterol synthesis and absorption: Lathosterol and phytosterols in Dutch twins and their parents

Significant familial aggregation was observed for plasma levels of lathosterol (an indicator of whole-body cholesterol synthesis) and plant sterols campesterol and β-sitosterol (indicators of cholesterol absorption) in 160 Dutch families consisting of adolescent mono- and dizygotic twin pairs and their parents. For lathosterol a moderate genetic heritability in parents and offspring (29%) was found. In addition, shared environment also contributed significantly (37%) to variation in plasma lathosterol concentrations in twin siblings. However, a model with different genetic heritabilities in the two generations (10% in parents and 68% in offspring) fitted the data almost as well. For plasma plant sterol concentrations high heritabilities were found. For campesterol heritability was 80% and for β-sitosterol it was 73%, without evidence for differences in heritability between sexes or generations. No influence of common environmental influences shared by family members was seen for either campesterol or β-sitosterol. Taken together, these results confirm and expand the hypothesis that individual differences in plasma levels of noncholesterol sterols are moderately (lathosterol) to highly (plant sterols) heritable

The effect of the apolipoprotein E phenotype on plasma lipids is not influenced by environmental variability: results of a Dutch twin study

We tested the influence of the apolipoprotein E (apoE) polymorphism on the intrapair differences in the levels of plasma cholesterol, plasma triglycerides, low density lipoprotein-cholesterol, apoB and apoE in monozygotic (MZ) twins, and estimated whether or not there was a interaction between the apoE polymorphism and environmental factors. In 65 MZ twin pairs, the intrapair differences in the measured lipoprotein parameters were similar in the different apoE phenotype classes. This indicates that the effect of the apoE polymorphism is not influenced by environmental variability between the MZ pair members and accordingly identifies the APOE gene as a "level" gene. © 1993 Springer-Verlag

Multicenter Comparison of Molecular Tumor Boards in The Netherlands: Definition, Composition, Methods, and Targeted Therapy Recommendations

Background: Molecular tumor boards (MTBs) provide rational, genomics-driven, patient-tailored treatment recommendations. Worldwide, MTBs differ in terms of scope, composition, methods, and recommendations. This study aimed to assess differences in methods and agreement in treatment recommendations among MTBs from tertiary cancer referral centers in The Netherlands. Materials and Methods: MTBs from all tertiary cancer referral centers in The Netherlands were invited to participate. A survey assessing scope, value, logistics, composition, decision-making method, reporting, and registration of the MTBs was completed through on-site interviews with members from each MTB. Targeted therapy recommendations were compared using 10 anonymized cases. Participating MTBs were asked to provide a treatment recommendation in accordance with their own methods. Agreement was based on which molecular alteration(s) was considered actionable with the next line of targeted therapy. Results: Interviews with 24 members of eight MTBs revealed that all participating MTBs focused on rare or complex mutational cancer profiles, operated independently of cancer type–specific multidisciplinary teams, and consisted of at least (thoracic and/or medical) oncologists, pathologists, and clinical scientists in molecular pathology. Differences were the types of cancer discussed and the methods used to achieve a recommendation. Nevertheless, agreement among MTB recommendations, based on identified actionable molecular alteration(s), was high for the 10 evaluated cases (86%). Conclusion: MTBs associated with tertiary cancer referral centers in The Netherlands are similar in setup and reach a high agreement in recommendations for rare or complex mutational cancer profiles. We propose a “Dutch MTB model” for an optimal, collaborative, and nationally aligned MTB workflow. Implications for Practice: Interpretation of genomic analyses for optimal choice of target therapy for patients with cancer is becoming increasingly complex. A molecular tumor board (MTB) supports oncologists in rationalizing therapy options. However, there is no consensus on the most optimal setup for an MTB, which can affect the quality of recommendations. This study reveals that the eight MTBs associated with tertiary cancer referral centers in The Netherlands are similar in setup and reach a high agreement in recommendations for rare or complex mutational profiles. The Dutch MTB model is based on a collaborative and nationally aligned workflow with interinstitutional collaboration and data sharing

Role of cyclic AMP in exocrine pancreatic secretion

Contains fulltext : mmubn000001_20268962x.pdf (publisher's version ) (Open Access)Promotor : S. Bonting180 p

Vastatins inhibit cholesterol ester accumulation in human monocyte-derived macrophages

Human monocyte-derived macrophages were incubated for 48 hours in Medium 199 with 1% human serum albumin, and with 100 μg acetyl low density lipoprotein (LDL) or β-very low density lipoprotein (β-VLDL), with or without various concentrations of compactin, lovastatin, simvastatin, or pravastatin. The mass of free (FC) and esterified (CE) cholesterol was determined, as well as the incorporation of [1-14C] acetate in sterols, that of [1-14C] oleate in CE, and that of [methyl-14C] choline in phospholipids. Moreover, we assessed the high-affinity association and degradation of 125I-labeled acetyl LDL. Compactin markedly decreased the cellular accumulation of CE induced by acetyl LDL or β-VLDL and increased the content of FC. Compactin also decreased the incorporation of [1-14C] oleate in CE (by 70-90%) in incubations with or without added lipoproteins. The half-maximal inhibitory concentration for this effect of compactin was 30 nM. Lovastatin and simvastatin were more potent, but pravastatin was about 100-fold less potent. Although compactin also caused a clear inhibition of cholesterol synthesis in the presence of acetyl LDL, the effect on CE formation did not seem to be related to decreased cholesterol synthesis, since this was already very low in the presence of acetyl LDL. Compactin did not affect the association and degradation of labeled acetyl LDL and also had no effect on the rate of cholesterol loss after preloading the cells with CE by incubation with acetyl LDL. However, compactin had a slight stimulatory effect on the synthesis of phosphatidylcholine and sphingomyelin when compactin was added to incubations in the presence of acetyl LDL. We conclude that vastatins can decrease the supply of FC toward the enzyme, acyl-coenzyme A:cholesterol acyltransferase, by trapping it in phospholipid-containing pools. Chemicals/CAS: compactin, 73573-88-3; mevinolin, 75330-75-5; pravastatin, 81131-74-0; simvastatin, 79902-63-9; Anticholesteremic Agents; Cholesterol Esters; compactin, 73573-88-3; Lipoproteins, LDL; Lipoproteins, VLDL; Lovastatin, 75330-75-5; Oleic Acid, 112-80-1; Oleic Acids; Phospholipids; Simvastatin, 79902-63-

Bile acids exert negative feedback control on bile acid synthesis in cultured pig hepatocytes by suppression of cholesterol 7α-hydroxylase activity

Feedback regulation of bile acid synthesis by its end products was studied in cultured hepatocytes of young weaned pigs. We previously showed that conversion of exogenous [14C] cholesterol into bile acids was suppressed by addition of bile acids to the culture medium. In the present study, the effects of bile acids on bile acid mass production and cholesterol 7α-hydroxylase activity were examined. Mass production of bile acids was strongly inhibited by addition of taurocholic acid (50 and 100 μmol/L) to the culture medium. The inhibitory action was exerted specifically on activity of cholesterol 7α-hydroxylase because conversion of [14C] 7α-hydroxycholesterol to bile acids by pig hepatocytes was not affected. Suppression of cholesterol 7α-hydroxylase activity after incubation of the hepatocytes with taurocholic acid was concentration- and time-dependent. Maximum suppression (-80%) was achieved after a 20 to 30 hr incubation of hepatocytes with 100 μmol/L of this bile acid. Decline of enzyme activity caused by 100 μmol/L taurocholic acid followed first-order kinetics with a half-life of 10 hr. Taurocholic acid had no direct effect on cholesterol 7α-hydroxylase activity in homogenates of hepatocytes as assessed by addition of the bile acid to the assay mixture. The effects of several other bile acids in a concentration of 100 μmol/L on cholesterol 7α-hydroxylase activity were examined in 48 hr incubations. Glycochenodeoxycholic and glycohyodeoxycholic acids, which are the major bile acids in pig bile, their unconjugated forms and also deoxycholic and cholic acid pronouncedly inhibited activity of the enzyme. In contrast, hyocholic acid almost failed to inhibit, whereas ursodeoxycholic acid was a weak inhibitor. It is concluded that bile acids, in physiological concentrations (i.e., as observed in portal blood), inhibit bile acid synthesis in cultured pig hepatocytes by suppression of cholesterol 7α-hydroxylase activity through a direct effect on the hepatocyte

Lipoprotein(a): relation to other risk factors and genetic heritability. Results from a Dutch parent-twin study

We measured plasma levels of lipoprotein(a) (Lp(a)) in a sample of 152 Dutch adolescent mono- and dizygotic twin pairs and their parents. The distribution of Lp(a) levels was skewed, with the highest frequencies at low levels and was similar for adult men and women and their children. The relationship of Lp(a) concentrations with other lipoprotein and apolipoprotein risk factors for coronary heart disease and with lathosterol, an indicator of whole-body cholesterol synthesis, was studied dependent on sex and generation. In mothers and children there was a small positive correlation between Lp(a) levels and plasma cholesterol and apolipoprotein (apo) B. In mothers and daughters there also was a correlation between Lp(a) and LDL cholesterol levels. No correlation was found between Lp(a) levels and plasma lathosterol, suggesting that there is no relationship between Lp(a) levels and cholesterol synthesis. Associations among family members, i.e. between monozygotic and dizygotic twins and between parents and offspring were used to study familial transmission of Lp(a) levels. Results showed that almost all of the variance in Lp(a) concentrations was accounted for by genetic heritability. A small, but significant, sex difference in heritability was observed, but heritabilities were the same in parents and offspring. Heritability estimates were 93% for females and 98% for males. No evidence was found for assortative mating or for the influence of a shared family environment. These results indicate that nearly all variance in Lp(a) concentrations that is not accounted for by the apo(a) size polymorphism, is also under genetic control

On the magnetic phase diagram of PbSnMnTe; carrier induced magnetism (abstract)

PbySn1-x-yMnxTe in various compositions, including Sn1-xMnxTe, displays an intriguing phase diagram which includes the carrier concentration p as an important parameter. A ferromagnetic state was found to exist only above a critical concentration pc3×1020 cm−3 at which a heavy hole band will be filled and starts to contribute to the RKKY interaction between the Mn ions.1 The present contribution deals with the magnetic phase diagram for low Mn concentrations (&lt;3%) as a function of the carrier density. The low temperature magnetic properties of PbSn(Mn)Te and Sn(Mn)Te were studied by means of magnetization, susceptibility and specific heat. In analogy with the existing results for other compositions, a ferromagnetic state is observed (Tcᶱ2-3 K), for p exceeding pc. However, for extremely high carrier densities, p 1021 cm−3, the data show a substantial deviation from what is commonly observed. This is characterized by a significant drop of Tc well below ᶱ and a rather broad maximum in the specific heat. Tentatively this transformation at higher p might be attributed to a ferromagnetic (F) to spin glass like transition, which, qualitatively, is in harmony with the competitive balance between ferro and antiferromagnetic (AF) exchange characteristic for the simple RKKY interaction: an increasing wave number (p1/3) will increase the number of antiferromagnetically long range coupled ions, at the expense of the strong ferromagnetic coupling between Mn2+ at shorter distances. Moreover, the mean distance between the Mn ions for x=0.02 is such that this delicate interplay between F and AF coupling should be observable.</p